Glucokinase (sometimes to be abbreviated to as GK in the present specification) (EC2.7.1.1) is one of the four kinds of hexokinases found in mammals, and is also called hexokinase IV. GK is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate, which is the first step of glycolysis. GK is mainly present in the pancreatic β cell and the liver, and acts in the pancreatic β cell as a sensor of extracellular glucose concentration that defines the glucose-stimulated insulin secretion. In the liver, the enzyme reaction of GK becomes a rate determining factor and regulates glycogen synthesis and glycolysis. The three hexokinases (I, II, III) other than GK reach the maximum enzyme activity at a glucose concentration of 1 mM or below. In contrast, GK shows low affinity for glucose and has a Km value of 8-15 mM which is close to a physiological blood glucose level. Accordingly, GK-mediated promotion of intracellular glucose metabolism occurs, which corresponds to blood glucose changes from normal blood glucose (5 mM) to postprandial hyperglycemia (10-15 mM).
The hypothesis proposed by Matschinsky et al. in 1984 that GK acts as a glucose sensor in the pancreatic β cell and hepatocytes has been demonstrated by the analysis of glucokinase transgenic mouse in recent years (see J. Biol. Chem., 1995, vol. 270, page 30253-30256; J. Biol. Chem., 1997, vol. 272, page 22564-22569; J. Biol. Chem., 1997, vol. 272, page 22570-22575; NIPPON RINSHO, 2002, vol. 60, page 523-534; and Cell, 1995, vol. 83, page 69-78). That is, GK heterozygous deficient mouse showed a hyperglycemic condition, and further, a disordered glucose-stimulated insulin secretion response. GK homozygous deficient mouse dies shortly after birth with manifestations of marked hyperglycemia and urinary sugar. On the other hand, GK overexpressed mouse (hetero type) showed decreased blood glucose level, increased blood glucose clearance rate, increased liver glycogen content and the like. From these findings, it has been clarified that GK plays an important role in the systemic glucose homeostasis. In other words, decreased GK activity causes insulin secretion failure and lower liver glucose metabolism, which develops impaired glucose tolerance and diabetes. Conversely, GK activation or increased GK activity due to overexpression causes promoted insulin secretion and promoted liver glucose metabolism, which in turn increases the systemic use of glucose to improve glucose tolerance.
In addition, it has been clarified froth the analysis of a report on GK gene abnormality mainly in the family of MODY2 (Maturity Onset Diabetes of the Young) that GK also acts as a glucose sensor in human, and plays a key role in glucose homeostasis (see Nature, 1992, vol. 356, page 721-722). In GK gene abnormality, due to the decreased affinity of GK for glucose (increased Km value) and decreased Vmax, the blood glucose threshold value of insulin secretion increases and the insulin secretory capacity decreases. In the liver, due to the decreased GK activity, decreased glucose uptake, promoted gluconeogenesis, decreased glycogen synthesis and liver insulin resistance are observed. On the other hand, a family with a mutation increasing the GK activity has also been found. In such family, fasting hypoglycemia associated with increased plasma insulin concentration is observed (see New England Journal Medicine, 1998, vol. 338, page 226-230).
As mentioned above, GK acts as a glucose sensor in mammals including human, and plays an important role in blood glucose regulation. On the other hand, control of blood glucose utilizing the glucose sensor system of GK is considered to open a new way to treat diabetes in many type 2 diabetes patients. Particularly, since a GK activating substance is expected to show insulin secretagogue action in the pancreatic β cell and glucose uptake promotion and glucose release suppressive action in the liver, it will be useful as a prophylactic or therapeutic drug for type 2 diabetes.
In recent years, it has been clarified that pancreatic β cell type glucokinase expresses locally in the feeding center (Ventromedial Hypothalamus: VMH) of rat brain. A subset of nerve cell present in VMH is called glucose responsive neuron, and plays an important role in the body weight control. From electrophysiological experiments, the neuron is activated in response to physiological changes in the glucose concentration (5-20 mM). However, since the glucose concentration sensor system of VHM is assumed to have a mechanism mediated by glucokinase as in the case of insulin secretion in the pancreatic β cell, different from pancreatic β cell and the liver, a pharmaceutical agent-capable of activating glucokinase of VHM has a possibility of providing not only a blood glucose corrective effect but also improvement of obesity.
As mentioned above, a pharmaceutical agent capable of activating GK is useful as a prophylactic or therapeutic drug for diabetes, diabetic complications, obesity and the like.
As the indole compound, the following compound has been reported.    (1) It has been reported that a compound represented by the formula:
wherein    R1, R2, R3, R4, R6 and R7 are independently a hydrogen atom, a halogen atom, nitro, —CN, —OH, —COOH, —CF3, —NR10R11 wherein R10 and R11 are independently a hydrogen atom, a C1-6 alkyl group, —CO—C1-6 alkyl, carboxy-C1-6 alkyl, —C—C1-6 alkyl-COOH, —SO2CH3, aryl group and the like, a C1-6 alkyl group, a C3-8 cycloalkyl group, a heteroaryl group and the like;    R5 is a C1-6 alkyl group and the like; and    A is an optionally substituted thiazolyl and the like,    is a glucokinase activator, which is useful for treatment of diabetes and the like (WO 2005/049019 (PTL 1)).    (2) It has been reported that a compound represented by the formula:
wherein    ring A is an optionally substituted 6-membered ring,    W is O, S(O)m wherein m is 0, 1 or 2, CR5R6 wherein R5 and R6 are independently a hydrogen atom or a C1-6 alkyl group, or NR7 wherein R7 is a hydrogen atom or R3′—Y′— wherein R3′ is an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, an optionally substituted amino group or an optionally substituted heterocyclic group, and Y′ is a bond, CO, S(O)q wherein q is 0, 1 or 2 or CR8′R9′ wherein R8′ and R9′ are independently a hydrogen atom or a C1-6 alkyl group,    Y is a bond, CO, S(O)p wherein p is 0, 1 or 2, or CR8R9 wherein    R8 and R9 are independently a hydrogen atom or a C1-6 alkyl,    R3 is an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, an optionally substituted amino group or an optionally substituted heterocyclic group,    Z is a bond, CO, O, S(O)n wherein n is 0 1 or 2, or NR10 wherein    R10 is a hydrogen atom or a C1-6 alkyl group,    R1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted mercapto group,    R2 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, an optionally substituted amino group or an optionally substituted heterocyclic group, or    R1 and R2 are bond to each other to form an optionally substituted ring,    is a glucokinase activator (WO 2006/112549 (PTL 2)).    (3) It has been reported that a compound represented by the formula:
wherein    R1 is an optionally substituted aryl group or an optionally substituted heteroaryl group;    R11 is an optionally substituted aryl group, a 5- to 7-membered aliphatic heterocyclic group, or an optionally substituted 5- or 6-membered heteroaryl group;    R2 is formyl, OH, a C1-6 alkyl group, —CH3-aFa, —OCH3-aFa wherein a is 1 to 3, amino, cyano, a halogen atom or —(CH2)1-4—OH;    R3 is a C1-6 alkyl group, —(CH2)1-6—OH, —C(O)—OC1-6 alkyl, —(CH2)1-6—OC1-6 alkyl, —(CH2)1-6—NH2, cyano, —C(O)—C1-6 alkyl, a halogen atom, a C2-6 alkenyl group, —O—C1-6 alkyl, —COOH or OH;    R4 is a hydrogen atom or a C1-6 alkyl group;    Y is a carbon atom or a nitrogen atom;    Z1 is —O—, —S—, —S(O)— or S(O)2—;    Z2 is —O—, —S—, —S(O)—, S(O)2— or —CH2— which is optionally substituted by a halogen atom, a C1-6 alkyl group and the like, or a single bond;    at least two of Y1, Y2, Y3 and Y4 are independently carbon atoms, and the others are a carbon atom or a nitrogen atom;    ring A is a heteroaryl group;    X is a carbon atom or a nitrogen atom;    m is 0 to 2; and    q is 0 to 2,    is a glucokinase activator, which is useful for treatment of diabetes, obesity and the like (WO 2007/037534 (PTL 3)).
However, none of the above-mentioned prior articles discloses the following formula (I).